Peptic ulcer disease is a major cause of morbidity and mortality in elderly and chronically ill populations. Despite major advances made about ulcer pathpgenesis, complications of peptic ulcers still represent a significant problem in at-risk populations, especially in the elderly and those with significant co-morbidities. Peptic ulceration represents a disturbance in the balance between aggressive factors (acid and pepsin) and defensive factors (mucosal bicarbonate secretion, blood flow, and mucus secretion). Of these, bicarbonate secretion is thought to be a primary defense mechanisms, due mainly to studies in which bicarbonate secretion is correlated to injury prevention, since, in general, increased bicarbonate secretion protects the mucosa from acid-induced injury. Nevertheless, the precise means by which an intrinsically leaky epithelium such as the duodenum can resist damage from intensely acid gastric juice remains unresolved. In the past few years, my laboratory has made the novel observation that provides unique insight into how duodenal villus epithelial cells,;the prime targets of gastric acid, can resist injury. We formulated the 'intracellular HCO3~'-hypothesis in which intracellular, not extracellular bicarbonate serves as the principal duodenal mucosal defense mechanism. To test this hypothesis, we have devised a series of experiments designed to 'uncouple' bicarbonate secretion and mucosal protection. Subjects with the disease cystic fibrosis, despite, copious gastric acid secretion and low duodenal pH, only rarely have duodenal ulcers. We believe that this is a result of bicarbonate being trapped in duodenal epithelial cells. We plan to test this hypothesis directly in mice deficient for the CFTR or cystic fibrosis gene product. Through the conduct of these studies, we hope to gain further insight into the mechanism of peptic ulceration, in the hopes of finding new treatments designed to prevent ulcer complications in our aging population, and to also gain additional insight into the pathogenesis of cystic fibrosis.